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University of Groningen
Hirschsprung's disease: early diagnosis and long-term outcomesMeinds, Rob Jelle
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CHAPTER 1
General introduction and aims
1 | General introduction and aims
Hirschsprung’s disease (HD) is a congenital defect of the intestines and is named after its
discoverer, Harald Hirschsprung. Hirschsprung’s report dates from 1887 and describes
the medical cases of two infants who had died from constipation in association with
extreme dilatation and hypertrophy of the colon.1 At the time, Hirschsprung mistakenly
believed that it was the dilated segment of the colon that was pathological. In 1949, more
than half a century later, Swenson and colleagues came to the conclusion that not the
dilated part of the colon was pathological, but the more distal, narrow part of the colon
(Figure 1).2 They reasoned that the extreme dilatation of the colon was caused by an inborn
obstruction at the distal end of the intestines that was blocking the passage of feces.
Backed by this theory, Swenson and Bill proceeded to remove the obstructing segment
of the intestines and achieved surprisingly good results.3 At around the same time as
Swenson and colleagues were undertaking their surgical experiments, the underlying
cause of HD was discovered by Whitehouse and Kernohan by comparing colon specimens
of HD patients with colon specimens of non-HD controls.4 In the former, they discovered
a complete absence of ganglion cells in both plexuses of the enteric nervous system, as
well as a profound hypertrophy of nerve bundles. These two discoveries revolutionized
the diagnosis and treatment of HD and greatly improved the morbidity and mortality
of patients who suffer from this previously fatal disease. Shortly after Swenson and Bill
reported on their surgical technique, other techniques were developed, including those
of Rehbein, Duhamel, and Soave.5–7
A B
C D
Figure 1Different types of Hirschsprung’s disease based on the length of the aganglionic intestines. A: Normal bowelB: Short-segment variant (up to the sigmoid)C: Long-segment variantD: Total colonic aganglionosis
10 | 11
Even today new discoveries are being made that help us to better understand the
pathophysiology and improve the treatment of HD. An overview of these discoveries is
given in this chapter, followed by the content and aims of this thesis.
ET IOLOGY
The main feature of HD is the absence of ganglion cells in the distal intestines. This was
first discovered by Whitehouse and Kernohan in 1948.4 The absence of ganglion cells,
known as aganglionosis, is thought to be the result of faulty migration of neural crest
cells during the embryonic development of the enteric nervous system.8 In normal fetal
development the neural crest cells migrate in a cranial-to-caudal direction between the
4th and 7th week of gestation, starting out from the esophagus and ending in the anal
canal.9 Currently, two theories exist that explain why these neural crest cells fail to reach
the distal intestines. The first theory proposes that the cells mature or differentiate into
ganglion cells too early during their migration.10 The second theory proposes that they
do reach their destination, but fail to differentiate, proliferate, or survive.11,12 No hard
evidence is available to confirm or refute either theory. The most likely explanation is
that faulty migration is the result of a combination of factors, which can differ between
individual patients.13 In between the aganglionic and ganglionic intestines is a segment
known as the transition zone. This zone contains a reduced number of ganglion cells and
marks the transition between the healthy and HD-affected intestines. It is considered
dysfunctional, similar to the aganglionic segment, because of its reduced number of
ganglion cells and decreased peristalsis.
PATHOPHYS IOLOGY
In HD the affected intestines are characterized by a constant increased tonus of the
smooth bowel muscles that blocks the passage of stool. In healthy intestines, smooth
muscles cells are innervated by sympathic (inhibitory) neurons and parasympathic
(excitatory) neurons. Jointly, these neurons are responsible for the motility of the gut
in conjunction with the complex architecture of the enteric nervous system (Figure 2).
The most important neurotransmitter responsible for inhibition is nitric oxide (NO). It
mediates relaxation of smooth muscle cells along with other inhibitors, such as vasoactive
intestinal polypeptide, and carbon monoxide.14 Additionally, excitatory neurons produce
neurotransmitters that mediate the contraction of smooth muscle cells, most importantly,
acetylcholine (ACh).14
1 | General introduction and aims
While HD is characterized by the absence of intrinsic ganglion cells in both plexuses,
there are still nerve fibers that innervate the smooth muscle cells of the affected
intestines (Figure 2). The exact origin of these nerve fibers is unknown. It is thought that
they have an extrinsic origin, such as the pelvic nerve plexus, and proliferate into the
bowel wall because of their failure to connect with the absent, intrinsic ganglion cells of
the enteric nervous system.15 For unknown reasons, the release by these nerve fibers
of inhibitory neurotransmitters, such as NO, is decreased, while there is an increased
release of excitatory neurotransmitters, such as ACh.16,17 The increased excitation of the
smooth muscle fibers by ACh and the absence of inhibition by NO, are thought to be
responsible for the constant increased tonus of the intestines and the lack of propagation
of peristaltic waves in HD.18
Another consequence of enteric nervous system abnormalities in patients with HD is
the absence of the rectoanal inhibitory reflex.19 In healthy bowels this reflex is responsible
for the relaxation of the internal anal sphincter upon rectal distension and stimulation
(Figure 3A). Relaxation of the internal anal sphincter is vital for the smooth passage of stool.
Normal innervation Hirschsprung’s disease
Parasympathetic(excitatory)
Sympathetic(inhibitory) Unknown origin
Muscularis propriaLongitudinal muscle
Myenteric plexus
Circular muscle
SubmucosaSubmucosal plexus
MucosaMuscularis mucosae
Lamina propriaEpithelium
Intestinal lumen
AChSympathetic ganglia
NO
NO (-)
NO
NO (-)NO (-)
NO (-)
ACh
ACh (+)
ACh (+)
ACh (+)
ACh (++)
ACh (++)ACh (++)
ACh (++)
ACh
Figure 2A schematic illustration of the layers of the intestinal wall with normal innervation (left) and innervation in case of Hirschsprung’s disease (right). In normal innervation excitatory neurons and inhibitory neurons are balanced and coordinated by ganglion cells () of the enteric nervous system. In Hirschsprung’s disease ganglion cells are absent in both plexuses, while a proliferation of extrinsic nerve fibers of unknown origin is present. The increased release of acetylcholine (ACh) by these fibers, in combination with the absence of inhibition by nitric oxide (NO), is thought to be responsible for the constant increased tonus of the intestines seen in Hirschsprung’s disease.
12 | 13
Dilatation balloonpressure (mm Hg)
200
0200
0*
Anal sphincterpressure (mm Hg)
Dilatation balloonpressure (mm Hg)
Anal sphincterpressure (mm Hg)
200
2000
000:00
00:00
01:00
01:00
50 mL
A
B
50 mL
Duration (minutes)
Duration (minutes)
C
Figure 3Anorectal manometry measurements.A: Measurement in a healthy control showing a rectoanal inhibitory reflex (asterisk) following rectal dilatation (arrowhead).B: Measurement in a patient with Hirschsprung’s disease showing no response in anal sphincter pressure following rectal dilatation. C: Illustration of the anorectal manometry catheter with a dilatation balloon at the tip of the catheter. The catheter is equipped with a pressure sensor at its tip to measure the dilation balloon pressure, as well as multiple pressure sensors at the level of the anal canal to measure changes in sphincter pressure.
1 | General introduction and aims
Consequently, the absence of this reflex in HD contributes to the constipation complaints
experienced by HD patients (Figure 3B). The absence of the rectoanal inhibitory reflex in
HD was first reported by Schnaufer and collegues20 and Lawson and Nixon21 in 1967, and
was later revealed to be caused by a lack of NO-producing inhibitory neurons.22
CLASS IF ICAT ION
The classification of HD depends on the length of intestinal aganglionosis, which in turn
depends on the developmental stage at which the migration of neural crest cells fails. If
migration fails in an early stage of embryonic development, the aganglionic segment may
be as long as the complete colon and part of the small intestines. If it fails at a later stage,
the aganglionic segment may be limited to the anal canal and/or to the anal sphincter
alone. The following types of HD are distinguished: the short-segment variant limited to
the rectum and sigmoid (roughly 80% of the patients), the long-segment variant up to the
splenic flexure or transverse colon (15%) and lastly, the total colonic variant (5%) (Figure
1).
In addition, there is a rare variant of HD, known as internal anal sphincter achalasia,
previously ultrashort HD, in which aganglionosis is limited to the anal sphincter. This
variant is characterized by normally innervated intestines but an absent rectoanal
inhibitory reflex. Preferably this variant is treated conservatively with laxatives.23 Lastly,
the most extreme and rare variant of HD is total intestinal aganglionosis. Patients
suffering from this type of HD have a very poor prognosis and the mortality rate is high.24
CL IN ICAL PRESENTAT ION
HD is a relatively rare cause of constipation and occurs in an estimated 1 to 2 cases per
10.000 live births.25–27 Boys are affected more often than girls, especially in case of the
shorter variant of HD in which the male-to-female ratio is 3:1.25,28
In the majority of the patients, HD presents shortly after birth with a failure to
pass meconium during the first 24 to 48 hours. Nowadays, on account of this early
presentation and overall increased awareness of the disease, HD is diagnosed in the
neonatal period in 91% of the patients.29 While a failure to pass meconium during the
first 48 hours is not uncommon in otherwise healthy newborns, other symptoms such
as a distended abdomen, feeding intolerance, and bilious vomiting often contribute to
raising the suspicion of HD. Despite increasingly earlier diagnoses, still approximately
5% of patients with HD are diagnosed after the first year of life.25 Especially patients with
a shorter segment of aganglionosis, who suffer less severe symptoms of constipation,
14 | 15
are at higher risk of being diagnosed at a later age.30 Patients in whom the disease has
gone unnoticed present with symptoms such as chronic constipation with intermittent
episodes of diarrhea, acute enterocolitis, or a sigmoid volvulus.31–33
Several other diagnoses may be associated with a delayed meconium passage and
therefore mimic the symptoms of constipation seen in HD. Important diagnoses that
should be considered in the differential diagnosis are: meconium ileus caused by cystic
fibrosis, intestinal atresia, malrotation, anorectal malformation, and small left colon
syndrome (associated with maternal diabetes). Additionally, several systemic disorders
should be kept in mind as they could also be responsible for constipation, for example:
electrolyte disorders, hypothyroidism, or constipation caused by maternal medication or
drug use.
While most cases of HD seem to occur sporadically and isolated, it is estimated that
10% to 20% of the cases present with associated congenital anomalies, predominantly
in the gastrointestinal tract, cardiovascular system, and urinary tract.25,26,34 Chromosomal
anomalies are also often seen in patients with HD. Especially the connection with Down
syndrome seems significant, as Down syndrome accounts for 94% of all chromosomal
anomalies in HD and has an incidence of 6% to 9% in the HD patient population.25,26,34
DIAGNOST IC INVEST IGAT IONS
While clinical presentation only suggests HD, the final diagnosis must be confirmed by
the outcomes of rectal suction biopsy, anorectal manometry, and/or contrast enema.
These three tests have been shown to have similar sensitivity and specificity, with the
rectal suction biopsy considered to be the gold standard.35,36
Rectal suction biopsyThe rectal suction biopsy procedure entails extracting rectal tissue consisting of mucosal
and submucosal material with a rectal suction biopsy tube. Generally, the procedure can
be carried out without sedation or anesthesia. Rectal tissue is extracted at multiple levels
above the anal verge and sent to a pathology laboratory for histologic examination. The
tissue is examined for the presence of intrinsic ganglion cells and the proliferation of
extrinsic nerve fibers. Absence of ganglion cells combined with proliferation of nerve
fibers is compatible with HD. Rectal suction biopsies should be taken at least 2 cm
from the edge of the pectinate line, as the first 1 to 2 cm physiologically have a reduced
number of ganglion cells.37 Furthermore, it is important to critically define the quality
of the biopsy, as the extracted tissue should consist of sufficient submucosa for the
appraisal of intrinsic ganglion cells.
1 | General introduction and aims
Over the years various staining techniques have been introduced to analyze the
tissue for intrinsic absence of ganglion cells and extrinsic proliferation of nerve fibers.
The variety of staining options implies that no uniform approach to the analysis of rectal
suction biopsies exists and, as a consequence, the approaches at different institutions
vary. One approach is to only assess tissue on the presence of ganglion cells by staining
with hematoxylin and eosin (H&E). Historically this proved effective but requires complete
dedication and much time of the responsible pathologist, because many sections have
to be inspected before a reliable diagnosis can be made. Another approach is to use
more advanced staining techniques to make diagnosing quicker and easier. One of these
staining techniques is acetylcholinesterase (AChE) histochemistry that was introduced by
Meier-Ruge in 1972.38 This technique can be used to judge the proliferation of extrinsic
nerve fibers in HD that are typically rich in ACh and AChE (the enzyme which catalyzes
the breakdown of ACh). AChE histochemistry increases the specificity of the rectal suction
biopsy by reducing the number of false positive outcomes.36 Despite making the diagnosis
of HD quicker and easier, AChE histochemistry is generally considered to be a more
sophisticated staining technique making it less suitable perhaps for institutions without
high-end laboratory equipment. Besides, it has been shown that this attaining technique
is difficult to interpret in neonates, which possibly leads to a higher false negative rate
at these ages.39,40 Therefore, newer staining techniques have been introduced, such as
calretinin immunohistochemistry, which are believed to further increase the diagnostic
accuracy of the rectal suction biopsy.41 While there is increasing advocacy for calretinin
immunohistochemistry,42–44 a recent analysis pointed out that this technique might be
associated with higher risks of false positive diagnoses, leading to unnecessary surgical
intervention.45 These new staining techniques might not completely replace AChE, but
certainly constitute an important addition to the routine repertoire of stains used in the
diagnosis of HD.
While the rectal suction biopsy is considered safe and reliable a small risk of
complications, such as persistent rectal bleeding, remains.46,47
Anorectal manometryAnorectal manometry can be used to examine anorectal physiology, including the
presence of the rectoanal inhibitory reflex. As previously explained, absence of this reflex
is a distinguishing feature of HD (Figure 3A).19–21 The anorectal manometry procedure
consists of inserting a catheter, equipped with pressure sensors and a small dilatation
balloon at its tip, into the anal canal of the patient. The balloon is placed in the rectum and
inflated slightly to simulate stool and to stimulate the rectal wall. As the rectal balloon is
inflated the pressure sensors at the level of the anal canal should measure a decrease in
16 | 17
internal anal sphincter pressure, also known as the rectoanal inhibitory reflex (Figure 3B).
Several studies have demonstrated the value of anorectal manometry as a screening
tool for HD, especially on account of its being non-invasive and having little to no risks.48–51
It has been disputed, however, that it is generally more difficult to interpret in newborns,
which in turn increases the risk of false negative and false positive test results.36,48 As
a consequence, few pediatric surgeons still use anorectal manometry for the purpose
of diagnosing HD, while the majority opts for rectal suction biopsies as the diagnostic
procedure of first choice.52,53 Recent technological advances, however, such as the
introduction of new catheters and high-resolution anorectal manometry, have increased
diagnostic accuracy.54 Anorectal manometry could therefore still be a valuable screening
tool for HD, especially because it is non-invasive and its use could serve to reduce the
number of invasive rectal suction biopsies.
Contrast enemaThe last technique used in the diagnosis of HD is the contrast enema. This technique
entails injecting a barium enema followed by an abdominal X-ray. A contrast enema
carried out in a HD patient typically shows a contracted distal colon, a transition zone,
and a distended colon in the caudal direction due to obstruction. Unfortunately, this
characteristic image is not seen in all HD patients. For example, a contrast enema taken
in a patient with a total colonic or an ultrashort variant of HD does not show the transition
zone and the difference in intestinal caliber, which would lead to a false negative test
result. The contrast enema has therefore lost its popularity as a diagnostic technique
for HD, as its accuracy was shown to be inferior to anorectal manometry and rectal
suction biopsy.35,36 Accuracy also greatly depends on the expertise of the radiologist. For
example, forceful injection of the contrast will distend the bowel and diminish accuracy
of interpretation. It is therefore not uncommon to record a 24-hour delayed radiograph,
which negates this effect. Indeed, Wong and colleagues found that a delayed radiograph
can be useful to rule out HD.55 Nevertheless, they suggested that it remains necessary
to carry out a rectal suction biopsy to either exclude or confirm the diagnosis of HD. It
therefore remains questionable whether the outcome of a 24-hour delayed radiograph
following contrast enema actually has any clinical implications.
The contrast enema, despite its flaws as a diagnostic procedure, still remains the
only investigation that can be used to evaluate the extent of aganglionosis and helps
preoperative planning. A recent publication by Muller and colleagues, however, showed
that the correlation of the radiographic transition zone with the level of aganglionosis
remains low.56 Their conclusion was that a biopsy remains mandatory to define the
transition zone.
1 | General introduction and aims
SURGICAL TREATMENT
A surgical reconstruction is usually performed to treat HD after the diagnosis is established.
Reconstruction consists of removing the majority of the aganglionic intestines in order to
restore bowel functionality. Nowadays, there are two major kinds of surgical strategies:
the abdominal approach and the transanal approach.
The abdominal approach consists of surgical techniques such as the Swenson, Rehbein,
Duhamel, and Soave procedures (Figure 4).3,5–7 Most of these procedures have undergone
alterations and modifications over the years, including the addition of laparoscopy.57,58 In
1948, Swenson introduced a technique to resect aganglionic intestines.3 His procedure
consisted of mobilizing and resecting the complete aganglionic intestines followed by
an end-to-end anastomosis of normal colon to the anal canal. Many surgeons, however,
faced postoperative problems such as pelvic nerve damage as a consequence of this
surgical procedure. Hence, other techniques were introduced, such as the one described
by Rehbein.5 Rehbein’s procedure avoided the pelvic nerves by only resecting the
upper aganglionic colon. The remaining aganglionic rectum and anal canal were dilated
afterwards. This too was not entirely satisfactory and in turn led to newer techniques
such as the ones described by Duhamel6 and Soave.7 Duhamel opted for a retrorectal
1 cm 1 cm1 cm3-5 cm
2 cm
Swenson Rehbein Duhamel Soave
Figure 4A schematic illustration of four of the most common surgical procedures that use an abdominal approach. Swenson’s procedure consists of mobilizing and resecting the complete aganglionic intestines relatively close to the dentate line, followed by an end-to-end anastomosis of healthy colon to the anal canal. Rehbein’s procedure consists of resecting the upper aganglionic colon, leaving 3 to 5 cm of distal aganglionic colon in situ, which is usually dilated afterwards. Duhamel’s procedure consists of a retrorectal approach followed by a side-to-side anastomosis of healthy colon to the posterior of the aganglionated rectum. Finally, Soave’s procedure consists of dissecting a rectal mucosal tube off the submucosal plane after which the ganglionic colon is pulled through the rectal sleeve. Adapted from Figure 44-1 in the chapter on Hirschsprung Disease. In: Ziegler MM et al, editors. Operative Pediatric Surgery. New York, NY: McGraw-Hill Education; 2014.
18 | 19
approach followed by a side-to-side anastomosis of ganglionic colon to aganglionated
rectum thereby completely avoiding the pelvic nerves anterior of the rectum. Soave’s
solution to avoid damaging the innervation of the pelvic floor was to devise an endorectal
pull-through procedure whereby a rectal mucosal tube was dissected off the submucosal
plane.
The transanal approach that has gained in popularity over the last few years is the
transanal endorectal pull-through (TERPT) described by De la Torre-Mondragón and
Ortega in 1998.59 The TERPT procedure consists of a transanal pull-through of ganglionic
intestines followed by a very low, direct anastomosis just above the dentate line (Figure
5).59 The latter can be done by using a short aganglionic muscular cuff created by a
transanal submucosal dissection (Soave-like)59,60 or by a full-thickness dissection of the
bowel wall (Swenson-like).61 By avoiding extensive manipulation in the peritoneal cavity,
this approach is thought to reduce the risk of postoperative adhesions. At the same
time damage to the pelvic floor innervation is prevented by avoiding extensive pelvic
dissection outside the rectum. Short-term outcomes of this technique seem favorable.
A B C
Figure 5A schematic representation of the transanal endorectal pull-through (TERPT) procedure.A: The location of the intended transanal circumferential incision, approximately 5 mm above the dentate line, marked by the dotted line.B: An endorectal dissection is made following the submucosal plane of the rectum until the level of the peritoneal cavity is reached. Next, the division of the muscular rectal wall is continued circumferentially, freeing the intra-abdominal colon from the muscle sleeve. The colon is then pulled through the anus.C: The pulled-through aganglionic colon is resected and an anastomosis of the healthy colon and the anus is made.Adapted from Figures 2, 4, and 5 in the article Hirschsprung disease. Haricharan RN, Georgeson KE. Semin Pediatr Surg. 2008 Nov;17(4):266-75.
1 | General introduction and aims
Some studies reported outcomes comparable to other techniques and other studies
even reported better results.60,62–64 Nevertheless, concerns remain, such as that during
the TERPT procedure the anal sphincter may be damaged by overstretching.65 Despite
this concern, a manometric study performed by van Leeuwen and colleagues in 2002,
found no differences regarding sphincter functioning between abdominal and transanal
approaches.66 The authors subsequently concluded that the transanal approach did
not pose an increased risk of sphincter damage. A more recent study by Stensrud and
colleagues, however, showed that sphincter damage and incontinence are in fact seen
more often following the anal approach in comparison to the abdominal approach.67 It
is important to note, however, that for this technique extensive long-term clinical results
are not yet available. It remains to be seen what the impact of the different surgical
approaches is on long-term anorectal functioning and fecal continence.
LONG-TERM OUTCOMES
Despite the best surgical efforts, studies often emphasize that HD is an incurable disease.
This is illustrated by various reports reporting that after surgical reconstruction, a large
group of patients continue to suffer from defecation disorders, such as constipation
and fecal incontinence.68–72 To date, it is not clear why some patients experience more
complaints than others. What is clear, is that these disorders may have far reaching
consequences, because both constipation and fecal incontinence are known to negatively
influence the quality of life.73,74
ConstipationConstipation is the chief complaint of HD patients. Often the complaints are so severe that
surgical reconstruction of the affected intestines is required to restore bowel continuity.
Without this intervention, intestinal obstruction could eventually lead to abdominal
distension, Hirschsprung’s disease-associated enterocolitis, growth failure, and in severe
cases, mortality. Even after surgical reconstruction, however, the majority of HD patients
retain a lifelong tendency towards constipation.
The tendency towards constipation may have several causes. First, and most
importantly, patients with HD will never develop a functional rectoanal inhibitory
reflex.19–21 This reflex and subsequent relaxation of the internal anal sphincter are vital
for the smooth passage of stool. Second, incomplete resection may result in residual
aganglionic intestines that could continue to hinder the passage of stool. Last, constipation
is a common complaint in the general population with an estimated prevalence of 16%.75
After excluding secondary causes for constipation, the majority of these complaints can
20 | 21
be explained either as a functional defecation disorder (dyssynergic defecation), slow-
transit constipation, or irritable bowel syndrome.76 On account of the high prevalence of
these disorders in the general population, it is likely that these disorders may also play
a role in the constipation complaints of HD patients. Further research is necessary to
determine to what extent other causes of constipation play a role in the complaints of
patients with HD.
Fecal incontinenceFecal incontinence is a frequent complaint of patients with HD, particularly after surgical
reconstruction. The prevalence of fecal incontinence, mostly limited to soiling, in the
general population is estimated at approximately 8%,77 whereas it may be as high as 40%
in patients with HD.78,79 It has been postulated that the fecal incontinence complaints of
HD patients may be a consequence of damage to the anal sphincter or innervation of
the pelvic floor during surgery, or from a reduced rectal reservoir as a result of surgical
reconstruction.80 There are several known risk factors for poor fecal continence in HD
patients, such as total colonic aganglionosis and the combination of HD with Down
syndrome.68,81 Another potential risk factor for fecal incontinence may be constipation in
association with fecal incontinence, a phenomenon often seen in pediatric and geriatric
populations.82 Further research on this subject is needed because as the cause for fecal
incontinence in the majority of HD patients remains unclear.
Quality of lifeQuality of life plays an increasingly important aspect in the assessment of long-term
outcomes, especially in chronic illnesses such as HD. Quality of life is a broad concept,
subjective by definition. It is often subdivided into various domains, often including the
physical, psychosocial, and social domains, as well as environment, level of independence,
and spirituality. Defecation disorders, such as constipation and fecal incontinence, are
known to influence the quality of life.73,74 The prevalence of these disorders in HD patients
is relatively high68–72 and one may assume that it negatively influences their quality of life.
This line of thought has prompted various studies on the long-term functional outcomes
and quality of life in HD patients.70,72,83,84 Unfortunately, it is still unclear how these
complaints and their influence on quality of life develop with aging.83 Additional research
is therefore needed to determine how the influence of defecation disorders on quality of
life varies in different age groups.
1 | General introduction and aims
A IMS OF TH IS THES IS
Both the diagnosis and treatment of HD have improved vastly over the last few decades.
Nevertheless, diagnosing HD remains troublesome, especially in very young infants.
Recent studies have shown that the rectal suction biopsy is not entirely satisfactory and
that caution is required when interpreting the outcome. Although surgical techniques are
being perfected and outcomes are improving, proper follow-up studies are necessary to
assess the differences between the various techniques in terms of long-term functional
outcomes and quality of life.
From this follows the twofold aim of this thesis. First, to improve the diagnostic process of determining HD with the aim to increase accuracy and to reduce the number of invasive biopsy procedures. Second, to perform long-term follow-up studies of HD patients to assess their functional outcomes and quality of life.
The first part of this thesis focusses on the diagnostic process of determining HD,
starting with a study on the accuracy of rectal suction biopsies in Chapter 2. For this
study we investigated, in retrospect, all rectal suction biopsies performed at University
Medical Center Groningen between 1975 and 2011, and analyzed at what age rectal
suction biopsies gave an accurate diagnosis. On the basis of this study we hypothesized
that anorectal manometry could be both a viable and safe screening tool for HD, and
that it could be used to reduce the number of invasive rectal suction biopsy procedures
in the diagnosis of HD. Prospectively, we gathered the results of 105 patients suspected
of HD who had undergone anorectal manometry. The results of this study are presented
and discussed in Chapter 3. In our study on anorectal manometry we found that even
in patients with normally developed ganglion cells, that is patients in whom HD was
excluded on the basis of rectal suction biopsy, the rectoanal inhibitory reflex could be
absent at birth. We hypothesized that the absence of this reflex might play a role in
the constipation complaints experienced by these patients. In addition, we hypothesized
that this reflex might mature and develop after birth. The development of this reflex in
newborns and its role with regards to constipation complaints are discussed in Chapter 4. In Chapter 5, the last chapter in this part of the thesis, we describe two extraordinary
cases of HD. In these two patients the disease had gone unnoticed until adolescence,
when they both presented with a solitary rectal ulcer.
The second aim of this thesis is to assess the long-term functional outcomes of
HD patients. Traditionally, the main outcome parameters in the treatment of HD are
constipation and fecal incontinence, that is, the inability to evacuate and retain stool.
Unfortunately, the questionnaires currently available for assessing these complaints are
often limited in the number of items and focus on quality of life rather than on factors
22 | 23
that influence anorectal functioning.85–90 The second part of this thesis is therefore
dedicated to the detailed questionnaire we developed to assess anorectal functioning.
The contents, applicability, and validity of the questionnaire are explained in Chapter 6.
To obtain reference data for our study on HD patients, we performed an extensive survey
of the Dutch population, the analysis of which is presented in Chapter 7.
The third and last part of this thesis focuses on the long-term outcomes of HD
patients. Based on our clinical observations we hypothesized that a significant number
of HD patients who reach adulthood continue to experience functional complaints such
as constipation and fecal incontinence. To test this hypothesis we performed a study
together with all six pediatric surgery institutes in the Netherlands. The resulting nation-
wide, cross-sectional study consisted of investigating the medical records of all known
HD patients and inviting eligible patients to complete our newly developed questionnaire
on anorectal functioning and a questionnaire on quality of life. The results of this study
are discussed in Chapters 8 and 9. In Chapter 8 we analyze the results of the anorectal
functioning and quality of life questionnaires, with a subanalysis to determine factors
associated with poor outcomes, and an analysis on the influence of poor outcomes on
quality of life. In Chapter 9 we use a subgroup of patients collected from the nation-wide
study to perform a matched comparison of patients treated with the Duhamel procedure
and the TERPT procedure. In the final chapter of this section, Chapter 10, we report
on a study in which we show that dyssynergic defecation can play an important role
in the postoperative constipation complaints of HD patients. We hypothesized that not
all postoperative defecation complaints were attributable to HD and that dyssynergic
defecation – for which viable treatment options are available – may increase the severity
of the constipation in these patients.
Finally, we discuss the main findings of this thesis in a general discussion in Chapter 11, thereby reflecting on the hypotheses laid down at the beginning of the thesis. We also
discuss the implications of this work and directions for future research. A summary of
the main findings and conclusions is given in Chapters 12 and 13, in English and Dutch
respectively.
1 | General introduction and aims
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1 | General introduction and aims
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PART I
Early diagnosis of Hirschsprung’s disease
2 Infant’s age influences the accuracy of rectal suction biopsies for diagnosing of
Hirschsprung’s disease
3 Anorectal manometry may reduce the number of rectal suction biopsy
procedures needed to diagnose Hirschsprung’s disease
4 Immaturity of the rectoanal inhibitory reflex as a cause of severe constipation
in newborns
5 Solitary rectal ulcer syndrome as a sign of unrecognized Hirschsprung’s disease